CN107969116A - Hydrophilic particle, its manufacture method and the contrast agent using the particle - Google Patents
Hydrophilic particle, its manufacture method and the contrast agent using the particle Download PDFInfo
- Publication number
- CN107969116A CN107969116A CN201680040477.XA CN201680040477A CN107969116A CN 107969116 A CN107969116 A CN 107969116A CN 201680040477 A CN201680040477 A CN 201680040477A CN 107969116 A CN107969116 A CN 107969116A
- Authority
- CN
- China
- Prior art keywords
- particle
- hydrophobic
- hydrophilic
- organic dyestuff
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002245 particle Substances 0.000 title claims abstract description 195
- 238000000034 method Methods 0.000 title claims abstract description 36
- 239000002872 contrast media Substances 0.000 title claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- 239000000975 dye Substances 0.000 claims abstract description 84
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 83
- 239000003446 ligand Substances 0.000 claims abstract description 24
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 239000012071 phase Substances 0.000 claims description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 18
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 14
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 14
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 14
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 14
- 239000005642 Oleic acid Substances 0.000 claims description 14
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 13
- 229910000314 transition metal oxide Inorganic materials 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 10
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 10
- 125000001165 hydrophobic group Chemical group 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000003287 optical effect Effects 0.000 claims description 9
- -1 ruthenium radical Chemical class 0.000 claims description 8
- 230000010148 water-pollination Effects 0.000 claims description 8
- 239000006210 lotion Substances 0.000 claims description 7
- 238000002595 magnetic resonance imaging Methods 0.000 claims description 7
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 6
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 6
- 235000021314 Palmitic acid Nutrition 0.000 claims description 5
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 5
- 229940070765 laurate Drugs 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 3
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 229910000420 cerium oxide Inorganic materials 0.000 claims description 3
- 229910000428 cobalt oxide Inorganic materials 0.000 claims description 3
- IVMYJDGYRUAWML-UHFFFAOYSA-N cobalt(ii) oxide Chemical compound [Co]=O IVMYJDGYRUAWML-UHFFFAOYSA-N 0.000 claims description 3
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 claims description 3
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 claims description 3
- 229910001938 gadolinium oxide Inorganic materials 0.000 claims description 3
- 229940075613 gadolinium oxide Drugs 0.000 claims description 3
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 claims description 3
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 claims description 3
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 claims description 3
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 3
- 239000011787 zinc oxide Substances 0.000 claims description 3
- 239000012099 Alexa Fluor family Substances 0.000 claims description 2
- 229910000480 nickel oxide Inorganic materials 0.000 claims description 2
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 claims description 2
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical compound [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims 1
- 239000002105 nanoparticle Substances 0.000 description 76
- 229960004657 indocyanine green Drugs 0.000 description 65
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 65
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 35
- 230000005291 magnetic effect Effects 0.000 description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 238000003917 TEM image Methods 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- 235000013339 cereals Nutrition 0.000 description 8
- 238000002601 radiography Methods 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 6
- 229910052742 iron Inorganic materials 0.000 description 5
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 235000021322 Vaccenic acid Nutrition 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000010835 comparative analysis Methods 0.000 description 4
- 238000004043 dyeing Methods 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000002189 fluorescence spectrum Methods 0.000 description 4
- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 4
- 238000004020 luminiscence type Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 4
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000002583 angiography Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000002296 dynamic light scattering Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 3
- 235000020778 linoleic acid Nutrition 0.000 description 3
- 210000001165 lymph node Anatomy 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 240000002853 Nelumbo nucifera Species 0.000 description 2
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 2
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000005611 electricity Effects 0.000 description 2
- 235000021384 green leafy vegetables Nutrition 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002122 magnetic nanoparticle Substances 0.000 description 2
- 230000005389 magnetism Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000010399 physical interaction Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005979 thermal decomposition reaction Methods 0.000 description 2
- UWHZIFQPPBDJPM-BQYQJAHWSA-N vaccenic acid group Chemical class C(CCCCCCCCC\C=C\CCCCCC)(=O)O UWHZIFQPPBDJPM-BQYQJAHWSA-N 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- OAXOJAZGUNGBCG-KVVVOXFISA-N (z)-octadec-9-enoic acid;ytterbium Chemical compound [Yb].CCCCCCCC\C=C/CCCCCCCC(O)=O OAXOJAZGUNGBCG-KVVVOXFISA-N 0.000 description 1
- KTNPCRWSDFHUAT-KVVVOXFISA-N (z)-octadec-9-enoic acid;yttrium Chemical compound [Y].CCCCCCCC\C=C/CCCCCCCC(O)=O KTNPCRWSDFHUAT-KVVVOXFISA-N 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- UWHZIFQPPBDJPM-FPLPWBNLSA-M Vaccenic acid Natural products CCCCCC\C=C/CCCCCCCCCC([O-])=O UWHZIFQPPBDJPM-FPLPWBNLSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- LDDQLRUQCUTJBB-UHFFFAOYSA-N ammonium fluoride Chemical class [NH4+].[F-] LDDQLRUQCUTJBB-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- SQTJTENXYVXDLR-KVVVOXFISA-N erbium;(z)-octadec-9-enoic acid Chemical compound [Er].CCCCCCCC\C=C/CCCCCCCC(O)=O SQTJTENXYVXDLR-KVVVOXFISA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 description 1
- 238000001027 hydrothermal synthesis Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
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Classifications
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- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0023—Di-or triarylmethane dye
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- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
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- A—HUMAN NECESSITIES
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- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
- A61K49/0067—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle quantum dots, fluorescent nanocrystals
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
- A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
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Abstract
The present invention relates to hydrophilic particle, the manufacture method of the hydrophilic particle and the contrast agent using the hydrophilic particle.More specifically, hydrophilic particle according to the present invention can include：Hydrophobic particle and directly adsorb in the amphipathic organic dyestuff on the hydrophobic particle surface.Here, each hydrophobic particle includes：Centrophyten and the hydrophobic ligand for covering the centrophyten surface, and the amphipathic organic dyestuff can be acted on by hydrophobicity and combined with hydrophobic ligand.The hydrophilic particle can have the surface zeta potential lower than the surface zeta potential of amphipathic organic dyestuff.
Description
Technical field
Present invention disclosed herein is related to hydrophilic particle, the manufacture method of the hydrophilic particle and use, and this is hydrophilic
The contrast agent of property particle, wherein making the phase in version of the hydrophilic particle by using amphipathic organic dyestuff.
Background technology
Due to unique electrical property, magnetism and the optical property and its various functions of nano particle, thus nano particle because
Scientific interest and potential application and be widely studied.Since nano particle is expected to improve medical diagnosis and treatment, so nanometer
Grain causes sizable concern in the application of biomedical sector.
For nano particle biomedical sector practical application, in vivo with need to have at the same time in external application
Magnetic and fluorescence nano particle.From this view point, actively into being about to magnetic nanoparticle and organic/inorganic
The research of the multi-layer nano particle of phosphor in combination.As magnetic nanoparticle, the gadolinium nano particle mesh as paramagnetic material
It is preceding to be clinically widely used, and be known as the oxidation iron-based nano particle of superparamagnetic material and can be used as making
With the contrast agent of MRI.
However, the material for forming the core of this multi-layer nano particle is heavy metal mostly, therefore, should for biomedicine
With, it is necessary to be modified processing to the surface of nano particle.For example, by introducing silica on the surface of nano particle
Layer is come to improve the method for biocompatibility be representative.
The content of the invention
Technical problem
The present invention provides a kind of hydrophilic particle being modified using amphipathic organic dyestuff without surface.
Present invention also offers a kind of method for manufacturing hydrophilic particle, this method includes the use of amphipathic organic dyestuff
Phase in version method as boundary material.
Present invention also offers a kind of contrast agent for including the hydrophilic particle.
Technical solution
The hydrophilic particle conceived according to the present invention can include hydrophobic particle and directly adsorb in hydrophobic particle
Amphipathic organic dyestuff on surface.In this case, hydrophobic particle includes centrophyten and covers the table of centrophyten
The hydrophobic ligand in face, and amphipathic organic dyestuff can be acted on by hydrophobicity and combined with the hydrophobic ligand.It is hydrophilic
Property particle surface zeta potential can be less than amphipathic organic dyestuff surface zeta potential.
In one embodiment, the centrophyten includes transition metal oxide, and the hydrophobic ligand can
To include aliphatic acid.
In one embodiment, the transition metal oxide can be selected from by iron oxide, manganese oxide, titanium oxide, oxygen
Change the group that nickel, cobalt oxide, zinc oxide, cerium oxide and gadolinium oxide are formed.
In one embodiment, the aliphatic acid can be selected from by oleic acid, laurate, palmitic acid, linoleic acid and tristearin
The group that acid is formed.
In one embodiment, the centrophyten is upper conversion particles, and the hydrophobic ligand can include
Aliphatic acid.
In one embodiment, the upper conversion particles can be selected from by " NaYF4:Yb3+, Er3+”、“NaYF4:Yb3+,
Tm3+”、“NaGdF4:Yb3+, Er3+”、“NaGdF4:Yb3+, Tm3+”、“NaYF4:Yb3+, Er3+/NaGdF4”、“NaYF4:Yb3+,
Tm3+/NaGdF4”、 “NaGdF4:Yb3+, Tm3+/NaGdF4" and " NaGdF4:Yb3+, Er3+/NaGdF4" form group.
In one embodiment, the aliphatic acid can be selected from by oleic acid, laurate, palmitic acid, linoleic acid and tristearin
The group that acid is formed.
In one embodiment, the amphipathic organic dyestuff can be selected from by rhodamine, BODIPY, Alexa
The group that Fluor, fluorescein, cyanine, phthalocyanine, azo-based dye, ruthenium radical dye and their derivative are formed.
In one embodiment, the amphipathic organic dyestuff can include hydrophilic radical and dredge in the molecule thereof
Water-based group, the hydrophilic radical selects the group that free carboxyl group, sulfonic group, phosphonate group, amido and alcohol radical are formed, described hydrophobic
Property group be selected from the group that is made of aromatic hydrocarbon and aliphatic hydrocarbon.
In one embodiment, the surface zeta potential of the amphipathic organic dyestuff can work as amphipathic organic dyestuff
The value measured during individualism.
In one embodiment, the surface zeta potential of the hydrophilic particle can be negative electrical charge.
In one embodiment, the average diameter of the hydrophilic particle can be more than the flat of the hydrophobic particle
Equal diameter.
It may include steps of according to the method for the manufacture hydrophilic particle of another inventive concept：Preparation has been dispersed in
Hydrophobic particle in machine phase, and the hydrophobic particle in organic phase mixed with the amphipathic organic dyestuff in water phase with
Form hydrophilic particle.In this case, amphipathic organic dyestuff can directly adsorb on the surface of hydrophobic particle with
It is the hydrophilic particle being dispersed in water phase by hydrophobic particle phase in version.
In one embodiment, the mixing of the hydrophobic particle and the amphipathic organic dyestuff can include inciting somebody to action
The hydrophobic particle in the organic phase is added in the amphipathic organic dyestuff in the water phase and to described
The mixture of hydrophobic particle and the amphipathic organic dyestuff is ultrasonically treated to form oil-in-water (O/W) lotion.
In one embodiment, the organic phase can include organic solvent, the organic solvent be selected from by chloroform,
The group that hexamethylene, hexane, heptane, octane, isooctane, nonane, decane and toluene are formed.
In one embodiment, the hydrophobic particle includes hydrophobic ligand, and the amphiphilic in its surface
Property organic dyestuff can be acted on by hydrophobicity and being combined with the hydrophobic ligand.
In one embodiment, the method can further include：After the hydrophilic particle is formed, structure is evaporated
Into the organic solvent of the organic phase.
Hydrophilic particle can be included according to the contrast agent of another inventive concept.In this case, the hydrophily
Grain can include the amphipathic organic dyestuff on hydrophobic particle and the surface for directly adsorbing in hydrophobic particle.Hydrophily
The surface zeta potential of particle can be less than the surface zeta potential of amphipathic organic dyestuff.
In one embodiment, contrast agent can be used for magnetic resonance imaging, optical imagery or magnetic resonance imaging and light
Study picture.
Beneficial effect
The hydrophilic particle conceived according to the present invention can pass through the amphipathic organic dyestuff on its surface and center
The combination of particle and there are two kinds of radiographies.In addition, the hydrophilic particle conceived according to the present invention has high-biocompatibility
And the stability for the organic dyestuff for being attached to its surface can be improved.In addition, the hydrophilic particle conceived according to the present invention
Manufacture method can simply and quickly be carried out by phase in version method, and the surface without particle is modified and surface is lived
Property agent.
Brief description of the drawings
Fig. 1 a are the sectional views for the hydrophilic particle for schematically showing the embodiment conceived according to the present invention.Fig. 1 b are
The amplification sectional view of the region M of Fig. 1 a；
Fig. 2 is the section of the manufacture method for the hydrophilic particle for schematically showing the embodiment conceived according to the present invention
Figure；
Fig. 3 shows the scattered TEM images of ferric oxide nanometer particle (IONP) and the analysis of size in organic solvent
As a result；
Fig. 4 shows the process purified using the magnetic force for the ferric oxide nanometer particle being dispersed in water phase；
Fig. 5 shows the ferric oxide nanometer particle (IONP that ICG is coated to) that the indocyanine green being dispersed in water phase is coated to
The analysis result of TEM image and size；
Fig. 6 is dispersed in water phase and is coated with the ferric oxide nanometer particle (IONP-ICG) of indocyanine green and pure Yin
The comparative analysis result of the surface charge of green (ICG) solution of diindyl cyanines；
Fig. 7 is indocyanine green (ICG), ferric oxide nanometer particle (IONP) and the ferric oxide nano for being coated with indocyanine green
The FT-IR analysis results of particle (IONP-ICG)；
Fig. 8 and Fig. 9 respectively illustrates the ferric oxide nanometer particle (IONP- for being dispersed in water phase and being coated with indocyanine green
) and the comparative analysis result of the absorption spectrum of pure indocyanine green (ICG) solution and fluorescence spectrum ICG；
Figure 10 shows that basis is dispersed in water phase and is coated with the various concentration of the ferric oxide nanometer particle of indocyanine green
T2 weighting MR model images and r2 values；
Figure 11 is the image and its MR images of fluorescence signal, wherein the ferric oxide nano of indocyanine green will be coated with
After grain is administered to the vola of mouse, the signal is at lymph node；
Figure 12 shows the scattered TEM image of upper conversion nano particle and the analysis result of size in organic solvent；
Figure 13 is luminescence generated by light (PL) image (UCNP for the upper conversion nano particle for being coated with indocyanine green；A, c) and by
It is covered with the fluoroscopic image (ICG of the upper conversion nano particle of indocyanine green；B, d)；
Figure 14 is the individual particle fluorogram for showing to be coated with the optical stability of the upper conversion nano particle of indocyanine green
Picture.
Specific embodiment
By reference to exemplary and attached drawing, it can be readily appreciated that the purpose of foregoing invention design, other mesh
, feature and advantage.However, present inventive concept can embody in different forms, and it should not be construed as being limited to this
The embodiment that text illustrates.Conversely, there is provided these embodiments are in order to make the disclosure thoroughly and complete, and by structure of the present invention
The scope of think of is fully conveyed to those skilled in the art.
In the accompanying drawings, for the clearness of present inventive concept, the size of the structure, thickness etc. are exaggerated.Moreover, should
It should be appreciated that although various elements can be described using term first, second etc. herein, these elements should not
It is limited by these terms.These terms are only used to distinguish an element and another element.It is described herein and exemplary each reality
Applying scheme also includes its complementary embodiment.Term "and/or" is used for before and after being included in what is listed herein
It is at least one in element.In the description, similar reference numeral refers to similar element.
Fig. 1 a are the sectional views for the hydrophilic particle for schematically showing the embodiment conceived according to the present invention.Fig. 1 b are
The amplification sectional view of the region M of Fig. 1 a.
With reference to Fig. 1 a and 1b, the hydrophily comprising hydrophobic particle 110 and amphipathic organic dyestuff 120 can be provided
Grain 100.Amphipathic organic dyestuff 120 can be directly adsorbed on the surface of hydrophobic particle 110.Can be by hydrophobic particle
Physical interaction between 110 and amphipathic organic dyestuff 120 causes absorption.
Hydrophobic particle 110 can include centrophyten 111 and the hydrophobicity being coated on the surface of centrophyten 111
Ligand 1 13.For example, hydrophobic ligand 113 can form individual layer and cover the surface of centrophyten 111.As another example,
Hydrophobic ligand 113 can uniformly or non-uniformly be attached to the inside and surface of centrophyten 111.Hydrophobic ligand 113 can
To assign centrophyten 111 hydrophobicity.Therefore, multiple hydrophobic particles 110 can be separately dispersed in organic solvent without
Need extra surfactant.
The embodiment conceived according to the present invention, centrophyten 111 can be transition metal oxide particles.That is, particle
Center 111 can include one or more selected from iron oxide, manganese oxide, titanium oxide, nickel oxide, cobalt oxide, zinc oxide, oxidation
The transition metal oxide of cerium and gadolinium oxide.Transition metal oxide (particularly iron oxide) may have under external magnetic field
It is magnetic.When external magnetic field is removed, remaining magnetism may disappear in transition metal oxide.Therefore, it is possible to reduce by
In the side effect that remaining magnetic force produces.In addition, transition metal oxide may be biodegradable in vivo, therefore its biology
Compatibility is probably excellent.The magnetic resonance imaging (MRI) that transition metal oxide can be used as treating cell is followed the trail of thin
Born of the same parents' marker material.
In another embodiment, centrophyten 111 can be upper conversion particles.Upper conversion particles can be when at it
The particle of luminous ray can be launched during upper irradiation near infrared ray.Upper conversion particles can be as doped with rare earth element
The particle of inorganic body.For example, upper conversion particles can include being selected from by " NaYF4:Yb3+, Er3+”、“NaYF4:Yb3+, Tm3 +”、 “NaGdF4:Yb3+, Er3+”、“NaGdF4:Yb3+, Tm3+”、“NaYF4:Yb3+, Er3+/NaGdF4”、“NaYF4:Yb3+, Tm3 +/NaGdF4”、“NaGdF4:Yb3+, Tm3+/NaGdF4" and " NaGdF4:Yb3+, Er3+/NaGdF4" form group in one kind or
It is a variety of.
Further, since hydrophobicity is presented in the surface of hydrophobic particle 110, so to hydrophobic particle 110 without special
Limitation, as long as the particle can disperse in organic solvent.
Hydrophobic ligand 113 can include aliphatic acid.For example, aliphatic acid can include being selected from by oleic acid, laurate, palm fibre
At least one of group that palmitic acid acid, linoleic acid and stearic acid are formed.
Amphipathic organic dyestuff 120 can be in the molecule thereof while have having for hydrophilic radical and hydrophobic group
Engine dyeing material.Hydrophilic radical can select the group that free carboxyl group, sulfonic group, phosphonate group, amido and alcohol radical are formed, hydrophobic group
The group being made of aromatic hydrocarbon and aliphatic hydrocarbon can be selected from.Specifically, amphipathic organic dyestuff 120 can be that fluorescence has engine dyeing
Material, and can be selected from by rhodamine, BODIPY, Alexa Fluor, fluorescein, cyanine, phthalocyanine, azo-based dye, ruthenium base
The group that dyestuff and their derivative are formed.For example, amphipathic organic dyestuff 120 can include indocyanine green.
(HI) is acted on by the hydrophobicity between the hydrophobic group and hydrophobic ligand of amphipathic organic dyestuff 120, two
Parent's property organic dyestuff 120 can be combined with hydrophobic ligand 113.Therefore, as described above, amphipathic organic dyestuff 120 can be straight
Absorption (or coated) is connect on the surface of hydrophobic particle 110.
The average diameter of hydrophilic particle 100 can be 10nm to 1000nm.In this case, hydrophilic particle 100
Average diameter can be more than hydrophobic particle 110 average diameter.It is hydrophilic in an embodiment of present inventive concept
The average diameter of property particle 100 can be twice of the average diameter of hydrophobic particle 110.
Hydrophilic particle 100 can have first surface zeta potential.When amphipathic 120 individualism of organic dyestuff, amphiphilic
Property organic dyestuff 120 can have second surface zeta potential.In this case, first surface zeta potential can be less than second surface ζ
Current potential.That is, compared with the amphipathic organic dyestuff 120 of individualism, hydrophilic particle 100 can be charge with what is born relatively
Matter.For example, first surface zeta potential can be negative electrical charge, and can be specially -100mV to -10mV.
As amphipathic organic dyestuff 120 is attracted on the surface of hydrophobic particle 110, amphipathic organic dyestuff 120
Hydrophilic radical may be more exposed to outside than hydrophobic group.Therefore, the hydrophily of amphipathic organic dyestuff 120
Group can be more distributed on the surface of hydrophilic particle 100 relatively.Therefore, with the amphipathic organic dyestuff of individualism
120 situation is compared, and the surface charge of hydrophilic particle 100 can have relatively negative value.
Hydrophilic particle 100 can be used as contrast agent by the amphipathic organic dyestuff 120 on its surface.
In one embodiment, when amphipathic organic dyestuff 120 is fluorescent organic dyes, hydrophilic particle 100 can carry out fluorescence
Radiography.In addition, the centrophyten 111 in hydrophilic particle 100 can have the function of radiography.For example, when centrophyten 111 wraps
When containing transition metal oxide, mr angiography are possible.In this case, hydrophilic particle 100 can have two kinds of radiographies
Function (mr angiography and fluoroscopic visualization), therefore can be used for the internal and external molecular imaging of biomedical sector.As another
One example, when centrophyten 111 is upper conversion particles, luminescence generated by light (PL) radiography is possible.In this case, it is close
Hydrophilic particles 100 can have the function of two kinds of radiographies (PL radiographies and fluoroscopic visualization).
Further, since hydrophilic particle 100 has hydrophily, therefore its biocompatibility can be excellent.Due to two
Parent's property organic dyestuff 120 acts on (HI) to be combined with hydrophobic particle 110 by hydrophobicity, it is possible to which improving amphipathic has
The fluorescent stability of engine dyeing material 120.
Fig. 2 is the section of the manufacture method for the hydrophilic particle for schematically showing the embodiment conceived according to the present invention
Figure.
, can by being ultrasonically treated to the mixture of the first solution 200 and the second solution 210 with reference to Fig. 1 a, 1b and 2
To form lotion 220 (S200).Specifically, it is possible, firstly, to prepare the first solution 200.First solution 200 can include dredging
Hydrophilic particles 110 and the organic solvent for being wherein dispersed with hydrophobic particle 110.In other words, hydrophobic particle 110 can divide
It is dispersed in organic phase.Various known methods, such as coprecipitation, thermal decomposition can be included the use of by preparing the first solution 200
Method, hydrothermal synthesis or microemulsion method.For example, the first solution 200 can be prepared by using thermal decomposition method.When using hot
During decomposition method, the fine dimension adjustment of hydrophobic particle 110 is possible, and the Size Distribution of hydrophobic particle 110 can
To be uniform, and the crystallinity of hydrophobic particle 110 can be improved.
Each hydrophobic particle 110 can include centrophyten 111 and is coated on the surface of centrophyten 111 thin
Water-based ligand 1 13.In one embodiment, centrophyten 111 can be transition metal oxide particle, in another implementation
In scheme, centrophyten 111 can be upper conversion particles.However, hydrophobic particle 110 is had no particular limits, as long as
The surface of grain has hydrophobicity so that particle can disperse in organic solvent.The detailed description of hydrophobic particle 110
Can be described identical with above with reference to Fig. 1 a and Fig. 1 b.Organic solvent can be selected from by chloroform, hexamethylene, hexane, heptan
One or more in the group that alkane, octane, isooctane, nonane, decane and toluene are formed, and it is had no particular limits.
The second solution 210 can be prepared.Can be molten to prepare second by mixing amphipathic organic dyestuff 120 and water
Liquid 210.In other words, amphipathic organic dyestuff 120 can be water phase.For example, amphipathic organic dyestuff 120 can be at it
There are the fluorescent organic dyes of hydrophilic radical and hydrophobic group at the same time in molecule.Amphipathic organic dyestuff 120 is retouched in detail
State can with above with reference to the described identical of Fig. 1 a and Fig. 1 b.
Can be by the way that the first solution 200 be added in the second solution 210, so as to prepare mixture.By using ultrasound
Ripple chip apparatus, can be mixed the supersound process of thing.Supersound process can carry out 10 seconds to 10 minutes.Therefore, first is molten
200 and second solution 210 of liquid is uniformly mixed to form oil-in-water (O/W) lotion 220.
While the first solution 200 and the second solution 210 are mixed, amphipathic organic dyestuff 120 can be adsorbed directly
On the surface of hydrophobic particle 110.Therefore, such hydrophilic particle 100 can be formed, the hydrophilic particle 100 is
The hydrophobic particle 110 of amphipathic organic dyestuff 120 is coated with its surface.Specifically, amphipathic organic dyestuff is passed through
Hydrophobicity effect (HI) between 120 hydrophobic group and hydrophobic ligand 113, amphipathic organic dyestuff 120 can be with dredging
Water-based ligand 1 13 combines.In the case of no chemical reaction and only by supersound process, there can be engine dyeing by amphipathic
Material 120 and the Physical interaction of hydrophobic particle 110 make amphipathic organic dyestuff 120 directly adsorb in hydrophobic particle
On 110 surface.
By stirring lotion 220, organic solvent evaporation (S210) can be made.Stirring can carry out 1 minute to 60 minutes.
As a result, hydrophilic particle 100 can be dispersed in water phase.Specifically, hydrophilic particle 100 is due to being present in it
The hydrophilic radical of amphipathic organic dyestuff 120 on surface and can be dispersed stably in water phase.In other words, do not having
In the case of having surfactant, the phase of hydrophobic particle 110 can be changed by amphipathic organic dyestuff 120.
Next, hydrophilic particle 100 can be purified (S220).Centrifugation can be included the use of by carrying out the purifying
Or use magnetic force.For example, can include centrifuging lotion 220 using centrifugation, and remove supernatant.The process can weigh
It is multiple to carry out, until the scattered amphipathic organic dyestuff 120 without being adsorbed on 100 surface of hydrophilic particle is removed.
, can be with when the centrophyten 111 of hydrophilic particle 100 is transition metal oxide particle as another example
Use magnetic force.It can include strength magnet being attached to lotion 220 using magnetic force, then remove supernatant.The process can weigh
It is multiple to carry out, until the scattered amphipathic organic dyestuff 120 without being adsorbed on 100 surface of hydrophilic particle is removed.
Can simply and quickly it be carried out by using phase transition method of the amphipathic organic dyestuff 120 as boundary material
The method for preparing hydrophilic particle 100 conceived according to the present invention, without carrying out surface modification to particle or using surface
Activating agent.
Hereinafter, for the ease of understanding present inventive concept, preferable experimental example will be described.It is, however, to be understood that
It is the purpose that following experimental example is merely to illustrate, without the scope for being intended to limit present inventive concept.
Experimental example 1：The synthesis of ferric oxide nanometer particle
By 36g iron oleates (Fe- oleates, 40mmol), 5.7g oleic acid (oleic acid, 20mmol) and 200g vaccenic acids (1-
Vaccenic acid) mixing.30 minutes are stirred the mixture under room temperature, decompression to remove the gas and water in mixture.With 3.3
DEG C/rate of heat addition of min heats the mixture to 320 DEG C.During this period of time, until keeping decompression shape before 200 DEG C
State, and keep inert atmosphere at a temperature of higher than 200 DEG C.At 320 DEG C, after which is stirred 30 minutes, remove
Heater, is slowly cooled to room temperature mixture.Afterwards, by volume for mixture 6 times of ethanol add into mixture with
Precipitate formed ferric oxide nanometer particle.Then, supernatant is removed, and separates ferric oxide nanometer particle, so that it divides again
Dissipate in n-hexane.The concentration of ferric oxide nanometer particle in n-hexane is adjusted to 10mg/ml (embodiment 1).
The nano particle of embodiment 1 is dropped on the copper grid for be coated with carbon to prepare sample, and with the high score of 200kV
Resolution ratio electronic microscope (Tecnai F20) obtains its transmission electron microscope (TEM) image.In addition, use granularity surface
Charge analysis instrument (Zetasizer Nano-ZS, Otsuka) is measured the size of the nano particle of embodiment 1.
Fig. 3 shows the scattered TEM images of ferric oxide nanometer particle (IONP) and the analysis of size in organic solvent
As a result.
With reference to Fig. 3, it can be seen that the TEM image (a) of the nano particle of embodiment 1.It can confirm that the nanometer of embodiment 1
Particle has highly uniform shape and average a diameter of about 13 to 14nm size.Due to the table of the nano particle of embodiment 1
Face is coated with oleic acid, therefore confirms that nano particle is well dispersed in organic solvent.However, the nano particle of embodiment 1
With the surface nature for preventing that nano particle is thoroughly dispersed in water phase.
In addition, the nanometer of the embodiment 1 being dispersed in n-hexane by dynamic light scattering (DLS) analysis (b) measurement
The size of grain is about 17nm.
Experimental example 2：It is coated with the preparation of the ferric oxide nanometer particle of indocyanine green
The ferric oxide nanometer particle (embodiment 1) of 1ml is scattered in n-hexane with the concentration of 10mg/ml, then to it
Middle addition 9ml methanol is so that ferric oxide nanometer particle precipitates.Then, supernatant is removed, adds 1ml chloroforms thereto so that oxygen
Change iron nano-particle redisperse.After 2mg indocyanine greens are dissolved in 4ml distilled water, 0.1ml is added thereto and is dispersed in
Ferric oxide nanometer particle in chloroform, and tip supersound process (tip ultrasonication) is carried out on it 1 minute with system
Standby first emulsion solution.The emulsion solution is vigorously stirred 5 minutes, until all chloroforms therein volatilize and remove.
Fig. 4 shows the process purified using the magnetic force for the ferric oxide nanometer particle being dispersed in water phase.
With reference to Fig. 4, the unadsorbed Yin on ferric oxide nanometer particle is removed using the magnetic property of ferric oxide nanometer particle
Diindyl cyanines are green.Specifically, the solution is made to be in close contact with strength magnet, and when ferric oxide nanometer particle is received near magnet
During collection, supernatant is removed, and adds 1ml distilled water thereto, by ferric oxide nanometer particle redisperse.Repeat the process 4 to
5 times, until the indocyanine green in solution is removed so that solution went clear.The indocyanine green of being coated with that will finally obtain
Ferric oxide nanometer particle is dispersed in 1ml distilled water (embodiment 2).
Experimental example 3：It is coated with the analysis of the feature of the ferric oxide nanometer particle of indocyanine green
The nano particle of embodiment 2 is dropped on the copper grid for be coated with carbon to prepare sample, and with the high score of 200kV
Distinguish that electron microscope (Tecnai F20) obtains its transmission electron microscope (TEM) image.In addition, use granularity surface electricity
Lotus analyzer (Zetasizer Nano-ZS, Otsuka) measures the size of the nano particle of embodiment 2.
Fig. 5 shows the ferric oxide nanometer particle (IONP that ICG is coated to) for being coated with indocyanine green being dispersed in water phase
TEM image and size analysis result.
It with reference to Fig. 5, can confirm that the nano particle of embodiment 2 is different from the ferric oxide nanometer particle of embodiment 1, implement
The nano particle of example 2 disperses without clustering phenomena (a) well in water phase.Due to the Yin as amphipathic organic dyestuff
Diindyl cyanines are green, and the surface conversion of ferric oxide nanometer particle is hydrophily, it is achieved that its phase in version.
After measured, the size of the nano particle for the embodiment 2 being dispersed in water phase and cell culture medium is respectively about 63nm
With 69nm (b).
Use the nanometer of granularity surface charge assay instrument (Zetasizer Nano-ZS, Otsuka) measure embodiment 2
The surface charge of grain.In addition, the surface charge of pure indocyanine green solution is measured using granularity surface charge assay instrument.
Fig. 6 is dispersed in water phase and is coated with the ferric oxide nanometer particle (IONP-ICG) of indocyanine green and pure Yin
The comparative analysis result of the surface charge of green (ICG) solution of diindyl cyanines.
When indocyanine green absorption is when on ferric oxide nanometer particle, the lipophilic group of indocyanine green is adsorbed in nano particle
Surface on so that its hydrophilic radical is relatively in the water phase.Therefore, the electricity of the indocyanine green around nano particle
Lotus may be more negative than the electric charge of pure indocyanine green solution.With reference to Fig. 6, when measuring and comparing the surface charge of two kinds of solution,
The electric charge for measuring pure indocyanine green solution is -25.1mV, and the electric charge for measuring the nano particle of embodiment 2 is -41.6mV.
Therefore, it can confirm that the surface charge of the nano particle of embodiment 2 is more negative than the surface charge of pure indocyanine green.
Prepare indocyanine green, the ferric oxide nanometer particle of embodiment 1 and embodiment 2 is coated with receiving for indocyanine green
Rice grain, is each in pulverulence.Its FT-IR is measured using surface reflection absorption ftir spectroscopy instrument (ALPHA-P, Bruker)
Spectrum.Fig. 7 is indocyanine green (ICG), ferric oxide nanometer particle (IONP) and is coated with the green ferric oxide nano of indoles diindyl cyanines
The FT-IR analysis results of particle (IONP-ICG).
Measured using UV, visible light sub-ray spectrometer (UV-2600, Shimadzu) and Fluorescence Spectrometer (FS-2, Sinco)
The nano particle and the Absorption and fluorescence spectrum of pure indocyanine green being dispersed in the water phase of embodiment 2.In addition,
The nano particle being dispersed in the water phase of embodiment 2 is prepared in the PCR pipe of various concentrations.Obtain the MR models of its T2 weightings
Image, and obtain each of which 1/T2 values.Obtained 1/T2 values and concentration ratio are used, calculates relaxation value (r2).
Fig. 8 and Fig. 9 respectively illustrates the ferric oxide nanometer particle (IONP- for being dispersed in water phase and being coated with indocyanine green
ICG) with the comparative analysis result of the Absorption and fluorescence spectrum of pure indocyanine green (ICG) solution.Figure 10 shows basis
The various concentration for the ferric oxide nanometer particle for being coated with indocyanine green being dispersed in water phase T2 weighting MR model images and
R2 values.
Indocyanine green be it is a kind of in structure while there is the amphipathic dyestuff of hydrophilic radical and hydrophobic group, because
, when indocyanine green is injected into blood, it can be moved for this, and protein expression present in blood be gone out extraordinary
Absorption property.That is, by hydrophobic interaction, (wherein the hydrophobic group of indocyanine green is adsorbed and is embedded into protein
Hydrophobic parts on), indocyanine green can have good absorption property.In this case, the absorption of indocyanine green
Spectrum may be after being combined to migrating on long wave length direction with protein.With reference to Fig. 8, when the nano particle of comparing embodiment 2
During with the absorption spectrum of pure indocyanine green solution, it can confirm that the absorbing wavelength red shift of nano particle of embodiment 2 to long wave
It is long.That is, the hydrophobic silica iron nano-particle that is coated with oleic acid is adsorbed and be coated in the hydrophobic parts of indocyanine green
On surface.
With reference to Fig. 9, in the case of the fluorescence spectrum of the nano particle of embodiment 2, can confirm that ought be energized into 765nm
When, sufficiently illustrate the near-infrared fluorescent signal in 800nm regions.
With reference to Figure 10, the relaxation rate r2 of the MR contrast abilities of the nano particle of measured expression embodiment 2 can confirm that
It is about 308mM-1s-1.From the result it has been confirmed that there is the nano particle of embodiment 2 mr angiography and near-infrared fluorescent to make at the same time
The feature of shadow.
The nanoparticles solution of 30 μ l embodiments 2 is expelled in the front foot bottom of BALB/c mouse.By using 830nm
Long pass filter and EM-CCD cameras are captured by irradiating 808nm laser to mouse the fluorescence signal that obtains.With identical
Mode, using 4.7T MRI (Bruker) obtain T2 weighting MR model images, and by cut lymph node obtain MR figure
Picture.As a result it is as shown in figure 11.Figure 11 is the image and its MR images of fluorescence signal, wherein the oxygen of indocyanine green will be coated with
After change iron nano-particle is administered to the vola of mouse, the signal is at lymph node.
Experimental example 4：The synthesis of upper conversion nano particle
By 779.4mg oleic acid yttrium (Y- oleates, 0.78mmol), 216.7mg oleic acid ytterbium (Yb- oleates,
0.20mmol), 21.6mg oleic acid erbium (Er- oleic acid, 0.02mmol), 8ml oleic acid and 200g vaccenic acids (1- vaccenic acids)
Mixing.30 minutes are stirred the mixture under room temperature, decompression to remove the gas and water in mixture.Then exist under reduced pressure
Mixture is slowly heated to 100 DEG C in 15 minutes, and stirs at 100 DEG C 40 minutes to obtain reaction solution.In indifferent gas
Reaction solution is slowly cooled to 50 DEG C under atmosphere, then 148mg ammonium fluorides and 10ml are dissolved with to the first of 100mg sodium hydroxides
Alcohol is injected into reaction solution.Afterwards, under an inert atmosphere at 50 DEG C, reaction solution is stirred 40 minutes.Then subtracting
Reaction solution is slowly heated to 100 DEG C by pressure, and is stirred 30 minutes at 100 DEG C.Afterwards, under an inert atmosphere when 1 is small
It is interior that reaction solution is slowly heated to 300 DEG C, and 30 minutes when stirring 1 is small at 300 DEG C.Hereafter, heater is removed, will be anti-
Answer solution to be slowly cooled to room temperature, then add 60ml ethanol thereto so that the upper conversion nano particle precipitation formed.
Then, supernatant is removed, makes conversion nano particle redisperse in 1ml hexanes.Add again in upward conversion nano particle solution
Enter 40ml ethanol so that particle precipitation, removes supernatant, to finally obtain upper conversion nano particle (NaYF4:Yb3+, Er3+) (real
Apply example 3).
Figure 12 shows the scattered TEM image of upper conversion nano particle and the analysis result of size in organic solvent.
With reference to Figure 12, it can be seen that the TEM image (a) of the nano particle of embodiment 3.It is possible thereby to confirm, embodiment 3
Nano particle there is uniform size and dimension.Since the nano particle of embodiment 3 is coated with oleic acid, so nano particle
It can be well dispersed in organic solvent.In addition, the result (b) analyzed according to DLS, can confirm that the nanometer of embodiment 3
The size of particle has the Size Distribution of 36.85 ± 9.22nm.The upper conversion nano particle (NaYF of embodiment 34:Yb3+, Er3+)
It is such optical contrast agents, it can be shone by absorbing the near infrared ray of 980nm in visible region.
Experimental example 5：It is coated with the preparation of the upper conversion nano particle of indocyanine green
Conversion nano particle (embodiment 3) on 1mg is dispersed in 1ml chloroforms.
After 2mg indocyanine greens are dissolved in 4ml distilled water, the embodiment 3 that 0.1ml is dispersed in chloroform is added thereto
Nano particle, and it is carried out tip be ultrasonically treated 1 minute, to prepare first emulsion solution.The emulsion solution is acutely stirred
Mix 5 minutes, until all chloroform volatilizations therein remove.Agitated solution is centrifuged, so that the nano particle of embodiment 3
Precipitation, removes supernatant, then adds distilled water thereto again.The process is repeated 4 to 5 times, until removing in solution
Indocyanine green so that solution went clear.The upper conversion nano particle for being coated with indocyanine green finally obtained is dispersed in 1ml
In distilled water (embodiment 4).
It can confirm that the nano particle of embodiment 4 is different from the upper conversion nano particle of embodiment 3, the nanometer of embodiment 4
Particle disperses without clustering phenomena well in water phase.The phase of upper conversion nano particle is also by as amphipathic organic
The indocyanine green of dyestuff and be changed into hydrophily.
Embodiment 6：It is coated with the analysis of the feature of the upper conversion nano particle of indocyanine green
The nano particle of embodiment 4 is spin-coated on glass slide to prepare sample.It can be photograph well in the nano particle of embodiment 4
The laser of 980nm is penetrated, uses upper conversion PL (luminescence generated by light) signal in the short bandpass filter measure visible region of 700nm.
785nm laser is radiated on the nano particle of embodiment 4 with identical position, and is measured using 830nm long pass filters
The fluorescence signal of indocyanine green.
Figure 13 is luminescence generated by light (PL) image (UCNP for the upper conversion nano particle for being coated with indocyanine green；A, c) and by
It is covered with the fluoroscopic image (ICG of the upper conversion nano particle of indocyanine green；B, d).In fig. 13, a and b represents identical first
Position (position 1), c and d represent the identical second place (position 2).
Reference Figure 13, sufficiently illustrates the PL signals and fluorescence signal of the nano particle of embodiment 4.It is possible thereby to really
Recognize and form indocyanine green coating on the surface of the nano particle of embodiment 4 well.Moreover, in the nano particle of embodiment 4
In the case of, by the combination of two kinds of optical contrast agents (upper conversion and fluorescence), dichroic optica radiography is possible.That is, use
Individual particle is possible in two making choice property of certain wave strong point observations.
Preparing spin coating thereon has the glass slide of nano particle of embodiment 4.A region of glass slide is selected, is used in combination
785nm laser Continuous irradiation 30 minutes.
Figure 14 shows the individual particle fluorogram of the optical stability for the upper conversion nano particle for being coated with indocyanine green
Picture.In fig. 14, a is up conversion signal, and b to the d in Figure 14 is the fluorescence signal that indocyanine green changes over time.
, can be true when relatively upper conversion PL signals (a) and fluorescence signal (b-d) changed over time with reference to Figure 14
Recognize：On it there are in the position (yellow arrows) of upper conversion nano particle, 30 minutes indoles cyanines afterwards are irradiated even in laser
Green fluorescence signal also continues to occur.On the other hand, can confirm that on it without in the position of nano particle：Indoles cyanines
Green fluorescence signal is reduced or disappeared relative to the earth after 30 minutes.This can be shown that, by being coated to Yin on nano particle
Diindyl cyanines are green, improve optical stability.As described above, the hydrophobic parts of indocyanine green and the surface phase interaction of nano particle
With and it is in connection, so as to combine the state of (non-flexible) in the structure.This state can be reduced due to indocyanine green
Photobleaching phenomenon caused by structure change, so as to improve optical stability.
Present inventive concept can provide the new aspect of phase in version method, because having used amphipathic organic dyestuff as use
In the boundary material of the medium of phase in version.In addition, the purposes as fluorescent contrast agent may be very big, because absorption can be improved
The fluorescent stability of amphipathic organic dyestuff on the surface of particle.
Claims (19)
1. a kind of hydrophilic particle, comprising：
Hydrophobic particle；With
Amphipathic organic dyestuff, it is directly adsorbed on the surface of the hydrophobic particle,
Wherein described hydrophobic particle includes centrophyten and the hydrophobic ligand on the covering centrophyten surface,
Wherein described amphipathic organic dyestuff is acted on by hydrophobicity and combined with the hydrophobic ligand, and
The surface zeta potential of wherein described hydrophilic particle is less than the surface zeta potential of the amphipathic organic dyestuff.
2. hydrophilic particle according to claim 1, wherein the centrophyten includes transition metal oxide, and
Wherein described hydrophobic ligand includes aliphatic acid.
3. hydrophilic particle according to claim 2, wherein the transition metal oxide is selected from by iron oxide, oxidation
The group that manganese, titanium oxide, nickel oxide, cobalt oxide, zinc oxide, cerium oxide and gadolinium oxide are formed.
4. hydrophilic particle according to claim 2, wherein the aliphatic acid is selected from by oleic acid, laurate, palmitic acid, Asia
The group that oleic acid and stearic acid are formed.
5. hydrophilic particle according to claim 1, wherein the centrophyten is upper conversion particles, and
Wherein described hydrophobic ligand includes aliphatic acid.
6. hydrophilic particle according to claim 5, wherein the upper conversion particles are selected from by " NaYF4:Yb3+,Er3+”、
“NaYF4:Yb3+,Tm3+”、“NaGdF4:Yb3+,Er3+”、“NaGdF4:Yb3+,Tm3+”、“NaYF4:Yb3+,Er3+/NaGdF4”、
“NaYF4:Yb3+,Tm3+/NaGdF4”、“NaGdF4:Yb3+,Tm3+/NaGdF4" and " NaGdF4:Yb3+,Er3+/NaGdF4" form
Group.
7. hydrophilic particle according to claim 5, wherein the aliphatic acid is selected from by oleic acid, laurate, palmitic acid, Asia
The group that oleic acid and stearic acid are formed.
8. hydrophilic particle according to claim 1, wherein the amphipathic organic dyestuff be selected from by rhodamine,
What BODIPY, Alexa Fluor, fluorescein, cyanine, phthalocyanine, azo-based dye, ruthenium radical dye and their derivative were formed
Group.
9. hydrophilic particle according to claim 1, wherein the amphipathic organic dyestuff is in the molecule thereof including hydrophilic
Property group and hydrophobic group, the hydrophilic radical selects the group that free carboxyl group, sulfonic group, phosphonate group, amido and alcohol radical are formed,
The hydrophobic group is selected from the group being made of aromatic hydrocarbon and aliphatic hydrocarbon.
10. hydrophilic particle according to claim 1, wherein the surface zeta potential of the amphipathic organic dyestuff is described
The value measured during amphipathic organic dyestuff individualism.
11. hydrophilic particle according to claim 1, wherein the surface zeta potential of the hydrophilic particle is negative electrical charge.
12. hydrophilic particle according to claim 1, wherein the average diameter of the hydrophilic particle is more than described hydrophobic
The average diameter of property particle.
13. a kind of method for manufacturing hydrophilic particle, including：
Prepare the hydrophobic particle being dispersed in organic phase；And
The hydrophobic particle in the organic phase is mixed to form hydrophily with the amphipathic organic dyestuff in water phase
Grain,
Wherein described amphipathic organic dyestuff is directly adsorbed on the surface of the hydrophobic particle with by the hydrophobic particle
Phase in version is the hydrophilic particle being dispersed in the water phase.
14. according to the method for claim 13, wherein mixing the hydrophobic particle and the amphipathic organic dyestuff bag
Include：
The hydrophobic particle in the organic phase is added in the amphipathic organic dyestuff in the water phase；And
The mixture of the hydrophobic particle and the amphipathic organic dyestuff is ultrasonically treated to form oil-in-water (O/W)
Lotion.
15. according to the method for claim 13, wherein the organic phase include organic solvent, the organic solvent selected from by
The group that chloroform, hexamethylene, hexane, heptane, octane, isooctane, nonane, decane and toluene are formed.
16. according to the method for claim 13, wherein the hydrophobic particle includes hydrophobic ligand in its surface, and
And
Wherein described amphipathic organic dyestuff is acted on by hydrophobicity and combined with the hydrophobic ligand.
17. according to the method for claim 13, further include：After the hydrophilic particle is formed, described in evaporation formation
The organic solvent of organic phase.
A kind of 18. contrast agent including hydrophilic particle, wherein the hydrophilic particle includes：
Hydrophobic particle；With
Amphipathic organic dyestuff, it is directly adsorbed on the surface of the hydrophobic particle,
And the surface zeta potential of wherein described hydrophilic particle is less than the surface zeta potential of the amphipathic organic dyestuff.
19. the contrast agent described in claim 18, its be used for magnetic resonance imaging, optical imagery or magnetic resonance imaging and optics into
Picture.
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| KR10-2015-0081804 | 2015-06-10 | ||
| KR1020150081804A KR101719263B1 (en) | 2015-06-10 | 2015-06-10 | Hydrophilic particle, a method for manufacturing the same, and contrasting agent using the same |
| PCT/KR2016/005323 WO2016200074A1 (en) | 2015-06-10 | 2016-05-19 | Hydrophilic particles, method for producing same, and contrast agent utilizing same |
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| EP (1) | EP3308802B1 (en) |
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| CN111634951A (en) * | 2020-06-09 | 2020-09-08 | 太原理工大学 | Preparation method of iron oxide/gadolinium oxide composite nanoparticles with uniformly distributed elements |
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| KR101880438B1 (en) * | 2017-04-14 | 2018-07-20 | 창원대학교 산학협력단 | PARTICLE INCLUDING UCNPs-LOADED PHOSPHATE MICELLE AND BEING USED FOR BIOIMAGING |
| WO2019010329A1 (en) * | 2017-07-06 | 2019-01-10 | The Trustees Of The University Of Pennsylvania | Amphiphilic dye-coated inorganic nanoparticle clusters |
| CN107782891A (en) * | 2017-10-19 | 2018-03-09 | 天津医科大学 | A kind of construction method of multi-functional upper conversion nano platform |
| KR102131757B1 (en) * | 2018-09-07 | 2020-07-09 | 한국과학기술연구원 | Dye-sensitized Upconversion nanophosphors and methods of synthesizing the same |
| CN111342117B (en) * | 2020-02-02 | 2022-10-28 | 江苏大学 | Super-hydrophobic solid electrolyte of lithium-air battery and preparation method thereof |
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| EP3308802B1 (en) | 2020-08-19 |
| US20180177899A1 (en) | 2018-06-28 |
| EP3308802A4 (en) | 2019-01-09 |
| KR20160145873A (en) | 2016-12-21 |
| WO2016200074A1 (en) | 2016-12-15 |
| KR101719263B1 (en) | 2017-03-24 |
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